Advances in perinatal care, including antenatal steroids, surfactant therapy and improved ventilator strategies, have markedly increased survival of extremely low birth weight infants. However, bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of perinatal morbidity and mortality. BPD is a major public health problem, occurring in over 10,000 new cases per year in the USA and causing prolonged hospitalizations, recurrent respiratory exacerbations, impaired lung function into adulthood, exercise intolerance, and pulmonary hypertension in survivors. BPD is characterized by abnormal lung structure due to an arrest of vascular and alveolar growth, but mechanisms contributing to the pathogenesis and optimal treatment of BPD remain poorly understood. Vascular endothelial growth factor (VEGF) is a potent mitogen and critical survival and maintenance factor for lung vascular endothelium. VEGF and its down-stream mediator, nitric oxide (NO), are essential for lung angiogenesis during early embryogenesis, but less is known about its roles and mechanisms of its effects later during development and in the setting of neonatal lung disease. Our past studies have shown that disruption of VEGF - NO signaling causes dysmorphic lung vascular growth and decreased alveolarization in experimental and clinical BPD. Inhibition of angiogenesis impairs alveolarization during lung development, and treatment with VEGF or inhaled NO (iNO) enhances endothelial survival, vascular growth and lung structure in diverse animal models of BPD. However, randomized clinical trials have failed to demonstrate that iNO therapy consistently prevents BPD in human preterm infants, as summarized in a recent NICHD Consensus Conference. Although several issues related to patient selection and study design may account for variability between studies, the failure of iNO therapy to consistently prevent BPD further highlights the importance of developing alternate strategies to preserve endothelial function and angiogenesis in premature infants. Since VEGF treatment improves vascular and alveolar growth in experimental BPD yet has no direct effects on airway epithelium, we hypothesize that in addition to NO activation, VEGF-induced enhancement of lung structure may be mediated through non-NO dependent pathways, and that these pathways may mediate critical epithelial-mesenchymal interactions that are essential for improving lung vascular and alveolar growth in BPD. Based on strong preliminary data, we further hypothesize that the effects of VEGF on lung structure are dependent upon stimulation of hepatocyte growth factor and enhanced retinoic acid production by vascular endothelium (angiocrine factors). In this renewal, we propose a series of integrative studies that incorporate physiologic, cell and molecular approaches towards understanding BPD.